CN102850273A - Novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam - Google Patents
Novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam Download PDFInfo
- Publication number
- CN102850273A CN102850273A CN2012103342336A CN201210334233A CN102850273A CN 102850273 A CN102850273 A CN 102850273A CN 2012103342336 A CN2012103342336 A CN 2012103342336A CN 201210334233 A CN201210334233 A CN 201210334233A CN 102850273 A CN102850273 A CN 102850273A
- Authority
- CN
- China
- Prior art keywords
- alpha
- caprolactam
- amino group
- amino
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to the technical field of medicine, and specifically relates to a novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam. With a method for splitting racemic alpha-amino-epsilon-caprolactam, (R)-alpha-amino-epsilon-caprolactam is obtained.
Description
Technical field
The present invention relates to the new synthetic method of compound (R)-alpha-amino group-ε-caprolactam, belong to technical field of pharmaceuticals.
Background technology
(R)-alpha-amino group-ε-caprolactam is the important intermediate of the broad spectrum antimicrobicide besifloxacin of synthetic treatment bacterial conjunctivitis, besifloxacin all is outside a kind of effective medicament to Gram-positive and gram negative pathogenic bacteria and other pathogenic bacterium to the fluoroquinolones resistance, in addition, it can also balance DNA gyrase and the activity of Topoisomerase Ⅳ, slow down the development of resistance, in clinical application, have obvious advantage than other xacin-series medicines.
The fractionation of document (Tertrahedron:Asymmetry 14 (2003) 3713-3718) report (±)-alpha-amino group-ε-caprolactam, the method is made solvent with methyl alcohol, make resolving agent with N-(tolysulfonyl)-L-Phe, (S)-alpha-amino group-ε-caprolactam makes crystal seed, add crystal seed at 48 ℃, 36-38 ℃ kept one hour, and was cooled to 20 ℃, keep one hour crystallization, suction filtration, dry after mother liquor is concentrated, add the isopropyl alcohol and water, stir, be heated to 75 ℃, be cooled to 66 ℃ and add crystal seed (R)-alpha-amino group-ε-caprolactam, 62-64 ℃ keeps crystallization in a hour, be cooled to 20 ℃, suction filtration.Separate salt and use water as solvent, 30% sodium hydroxide neutralizing acid.Total recovery is 36%, ee〉99.9%.The method needs the crystal seed of single configuration, and complicated operation, and yield is lower, because the finished product uv-absorbing is very weak, is unfavorable for that HPLC detects.For defects, this programme looks for another way, and has improved method for splitting, has obtained comparatively desirable effect.
Summary of the invention
The applicant has now developed the method for a kind of new fractionation (±)-alpha-amino group-ε-caprolactam, this method for splitting has solved the problem with crystal seed splits and split result can't detect with HPLC when obtaining (R)-alpha-amino group-ε-caprolactam of higher ee value.
In the amido protecting method described in the present invention, the protection reagent of use comprises triphenylmethyl chloride, cylite, chloroformic acid benzyl ester, is preferably triphenylmethyl chloride.
In the amido protecting method described in the present invention, employed solvent comprises methylene dichloride, trichloromethane, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, preferably uses trichloromethane to do reaction solvent.
In the method for splitting described in the present invention, employed resolving agent comprises L-(+)-tartrate, L-(+)-oxysuccinic acid, L-(+)-amygdalic acid, L-(+)-camphorsulfonic acid, preferably use L-(+)-amygdalic acid makes resolving agent.
In the method for splitting described in the present invention, the employed solvent of salify is trichloromethane.
In the method for splitting described in the present invention, salify control temperature of reaction is 0 ℃ to 70 ℃, is preferably 10 ℃ to 60 ℃.
In the method for splitting described in the present invention, separating the used reagent of salt is ammoniacal liquor.
Invention route equation:
4. embodiment
Referring to concrete embodiment the present invention is described, those skilled in the art can understand.The implementation example is only in order to illustrate the present invention, the practical range that it does not limit the present invention in any way.
Embodiment one: the preparation of (±)-α-(N-trityl group) amino-ε-caprolactam
Under the nitrogen protection, in the 500mL there-necked flask, add (±)-alpha-amino group-ε-caprolactam hydrochloride (8.3g, 50mmol), trichloromethane 150mL, triethylamine (14.5mL, 100mmol), stirring at room 30 minutes.Slowly drip the solution of the trichloromethane (90mL) that contains triphenylmethyl chloride (13.9g, 50mmol) under the agitation condition, after dropwising in 15 minutes, continue reaction 3 hours.Suction filtration, filtrate water are washed three times, and saturated common salt is washed once, anhydrous sodium sulfate drying organic phase, suction filtration, concentrated white solid.40 ℃ of forced air dryings of normal pressure get white solid 15.1g, yield 82%, m.p.:223-226 ℃.LC-MS：371.2?[M+1]
+。
Embodiment two: (R)-preparation of α-(N-trityl group) amino-ε-caprolactam L-(+)-mandelate
In the 500mL there-necked flask, add (±)-α-(N-trityl group) amino-ε-caprolactam (14.8g, 40mmol), chloroform 240mL, methyl alcohol 40mL stirred 30 minutes, and system becomes clarification.Methyl alcohol (40mL) solution that adds L-(+)-amygdalic acid (6.08g, 40mmol) stirs, and is heated to 50 ℃, keeps this temperature 1 hour.Be cooled to 20 ℃, kept this temperature 2 hours.The adularescent solid is separated out, and suction filtration gets white solid 8.78g, yield 84%, m.p.:196-197 ℃ after 40 ℃ of dryings of filter cake normal pressure.
Embodiment three: (R)-α-(N-trityl group) amino-ε-caprolactam preparation
In the 250mL there-necked flask, add (R)-α-(N-trityl group) amino-ε-caprolactam L-(+)-mandelate (4.39g, 8.4mmol), water 100mL, ammoniacal liquor (0.6mL, 8.4mmol) is heated with stirring to 50 ℃.Keep temperature 40 minutes, and be cooled to room temperature, suction filtration, filter cake washes twice with water, and 40 ℃ of dryings of filter cake normal pressure get white solid 2.87g, yield 92%, m.p.:223-224 ℃, LC-MS:371.2 [M+1]
+
Embodiment four: (R)-alpha-amino group-ε-caprolactam preparation
In the 250mL there-necked flask, add (R)-α-(N-trityl group) amino-ε-caprolactam (2.87g, 7.7mmol), water 100mL, sodium hydroxide (0.31g, 7.7mmol) water (20mL) solution, stirring at room 2 hours.Chloroform extraction, 6 N HCl extracted organic phase three times merge water, remove water under reduced pressure, get white solid, and 40 ℃ of dryings of normal pressure get white solid 1.20g, yield 95%.M.p.:292-294 ℃ (decomposition), [α] 25D+26.5 (c 4.01,1N HCl),
1H NMR (DMSO-
d 6 ) δ 1.21 (d,
J=14.4 Hz, 1H), 1.52-1.64 (m, 2H), 1.74-1.78 (m, 1H), 1.87-1.93 (m, 2H), 3.05-3.10 (m, 1H), 3.16-3.23 (m, 1H), 4.10 (d,
J=14.4 Hz, 1H), 8.12 (br s, 2H), 8.18 (br s, 1H).LC-MS：129.1?[M+1]
+。[α]
25 D?=?+26.5?(c?4.01,1N?HCl)。
Claims (8)
1. the method for a resolution of racemic alpha-amino group-ε-caprolactam (formula I),
It is characterized in that the alpha-amino group with protecting group protection racemize alpha-amino group-ε-caprolactam (formula I) commonly used; thereby obtain intermediate (formula II); this intermediate again with common have optically active resolving agent salify, separate salt; then deprotection obtains having optically active (R)-alpha-amino group-ε-caprolactam (formula III).
2. method according to claim 1 is characterized in that the used protecting group of alpha-amino protection is wherein a kind of of triphenylmethyl chloride, cylite, chloroformic acid benzyl ester.
3. method according to claim 1 is characterized in that the used solvent of alpha-amino group protective reaction is methylene dichloride, trichloromethane, tetrahydrofuran (THF), wherein one or more of Isosorbide-5-Nitrae-dioxane.
4. method according to claim 1, the temperature that it is characterized in that the alpha-amino group protection be 0 ℃ to the reflux temperature of solvent.
5. method according to claim 1 is characterized in that the used resolving agent of salify is selected from L-(+)-oxysuccinic acid, L-(+)-amygdalic acid, L-(+)-tartrate, L-(+)-wherein one or more of camphorsulfonic acid.
6. method according to claim 1 is characterized in that the used solvent of salify is methylene dichloride, trichloromethane, wherein one or more of methyl alcohol.
7. method according to claim 1, it is characterized in that separating the used reagent of salt is ammoniacal liquor or triethylamine.
8. method according to claim 1 is characterized in that the used ammonia solution reagent of Deprotection is sodium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103342336A CN102850273A (en) | 2012-09-12 | 2012-09-12 | Novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103342336A CN102850273A (en) | 2012-09-12 | 2012-09-12 | Novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102850273A true CN102850273A (en) | 2013-01-02 |
Family
ID=47397309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103342336A Pending CN102850273A (en) | 2012-09-12 | 2012-09-12 | Novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102850273A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103694174A (en) * | 2014-01-06 | 2014-04-02 | 南京工业大学 | Alpha-(N-benzyl)amino-epsilon-caprolactam compound as well as preparation method and application thereof |
-
2012
- 2012-09-12 CN CN2012103342336A patent/CN102850273A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103694174A (en) * | 2014-01-06 | 2014-04-02 | 南京工业大学 | Alpha-(N-benzyl)amino-epsilon-caprolactam compound as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108395443B (en) | Cyclic compounds inhibiting programmed death receptor ligand 1 and uses thereof | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| EP3337485B1 (en) | Crystalline forms of ibrutinib | |
| EP2213651B1 (en) | Resolution of 4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane | |
| CN102985416A (en) | Process of preparing a thrombin specific inhibitor | |
| CN102180892B (en) | Novel method for purifying cefmetazole sodium | |
| EP2743259A1 (en) | Method for purifying (s)-oxiracetam | |
| CN103396416A (en) | Preparation method of moxifloxacin impurity F | |
| EP2743258B1 (en) | Method for purifying levo-oxiracetam | |
| JP2009541291A (en) | Crystalline duloxetine hydrochloride | |
| CN109369424A (en) | A kind of purification process of dapoxetine hydrochloride | |
| CN104277053B (en) | A kind of preparation method of Cefodizime and its intermediate cefodizime acid | |
| CN102850273A (en) | Novel synthesizing method of (R)-alpha-amino-epsilon-caprolactam | |
| TW202024035A (en) | Novel process for the preparation of (-)-cibenzoline succinate | |
| CN102603592B (en) | Preparation method for (R)-1-benzyl-3-aminopyrrolidine and (S)-1-benzyl-3-aminopyrrolidine | |
| CN111362873B (en) | Synthetic method of gatifloxacin metabolite | |
| EP3122708B1 (en) | An improved process for the preparation of exametazime | |
| CN103113408A (en) | Novel method for preparing fosfomycin phenylethylamine | |
| CN105523957A (en) | Method for preparing Lacosamide by one-pot method | |
| CN105646284A (en) | Lacosamide synthesis method | |
| CN102863370A (en) | Novel synthetic method of antiepileptic drug levetiracetam | |
| EA015600B1 (en) | Ampa receptor potentiators | |
| CN104693177A (en) | Refining method of esomeprazole sodium | |
| ES2615637T3 (en) | Improved procedure for optical purification of esomeprazole | |
| EP3596048A1 (en) | Process for the separation of optical isomers of racemic 3-alkylpiperidine-carboxylic acid ethyl esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130102 |
|
| DD01 | Delivery of document by public notice |
Addressee: Song Xuemei Document name: Notification of Approving Refund |